Like other areas of the nervous system, the retina is subject to many acquired and inherited neuronal degenerative diseases. Since the retina provides the input for all visual sensory information to the brain, the loss of cells results in visual impairment and potentially complete blindness. Many retinal degenerative diseases affect only a subset of the retinal cells, although, frequently in more advanced disease, loss and reorganization of the entire retina can occur. It has long been thought that in humans there is no recovery of the degenerated cells; however, there is now increasing evidence that the mammalian retina has a limited capacity for neuronal regeneration, and some components of the regenerative response found in non-mammalian vertebrates are also present in mammals. In fish, new neurons of all types regenerate from Muller glia following retinal damage and they are functionally integrated into the existing circuitry. Regeneration is considerably more limited in birds and rodents, both in quantity and types of neurons generated. Although this may represent a vestigial regenerative response in homoeothermic vertebrates when compared with their cold- blooded relatives, Muller glia, the cellular source for regeneration, are present in all vertebrate retinas. Our recently published data and new preliminary unpublished data indicate that the regenerative response of Muller glia might be limited by inhibitors in their activation of a neurogenic pattern of gene expression. In this proposal we outline experiments to test specific hypotheses about the factors that limit regeneration from the Muller glia in the mammalian retina. The results of these experiments will provide a better understanding of the limits of the regenerative potential of mammalian Muller glia, and may lead to development of novel strategies for treatment of human retinal degeneration. PUBLIC HEALTH RELEVANCE: Like other areas of the nervous system, the retina is subject to many acquired and inherited neuronal degenerative diseases. Since regeneration of new retinal neurons does not occur in people, these diseases can leave them with permanent visual impairment. In this proposal we outline experiments to provide a better understanding of the limits of the regenerative potential of mammalian Muller glia, which may lead to development of novel strategies for treatment of human retinal degeneration.